WO2023005928A1 - Composé de 8-oxo-3-azabicyclo[3.2.1]octane ou sel de celui-ci, procédé pour le préparer et son utilisation - Google Patents

Composé de 8-oxo-3-azabicyclo[3.2.1]octane ou sel de celui-ci, procédé pour le préparer et son utilisation Download PDF

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WO2023005928A1
WO2023005928A1 PCT/CN2022/107932 CN2022107932W WO2023005928A1 WO 2023005928 A1 WO2023005928 A1 WO 2023005928A1 CN 2022107932 W CN2022107932 W CN 2022107932W WO 2023005928 A1 WO2023005928 A1 WO 2023005928A1
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Prior art keywords
alkyl
compound
oxa
cancer
azabicyclo
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PCT/CN2022/107932
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English (en)
Chinese (zh)
Inventor
程***
黄亚飞
周娟
王永辉
陈伟
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上海辉启生物医药科技有限公司
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Priority to KR1020247006386A priority Critical patent/KR20240041354A/ko
Priority to IL310412A priority patent/IL310412A/en
Priority to CA3227713A priority patent/CA3227713A1/fr
Priority to AU2022316931A priority patent/AU2022316931A1/en
Publication of WO2023005928A1 publication Critical patent/WO2023005928A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to a group of 8-oxa-3-azabicyclo[3.2.1]octane compounds used as ATR inhibitors, their preparation methods, their pharmaceutical compositions and their Use for treating or preventing ATR-related diseases.
  • DDR DNA Damage Response
  • ATR ataxia telangiectasia mutated and Rad3-associated kinase
  • ATM ataxia telangiectasia mutated kinase
  • DNA-PK DNA-dependent protein kinase
  • ATR is a member of the phosphatidylinositol kinase-related kinase (PIKK) protein family, and its main target is CHK1.
  • PIKK phosphatidylinositol kinase-related kinase
  • ATR inhibition Compared with healthy proliferating cells, tumor cells have higher DNA damage and replication stress. To survive replication and maintain cell division, they are more dependent on ATR for DNA repair. Therefore, by inhibiting ATR, the repair function of tumor cells can be inhibited, leading to increased DNA damage and replication stress that cannot be repaired, and eventually leading to tumor cell death, while not affecting or less affecting healthy proliferating cells, which constitutes ATR inhibition.
  • ATR inhibition has been considered as an important cancer treatment approach in recent years.
  • Standard cancer therapies such as radiation or chemotherapy work by inducing DNA damage, which is particularly toxic to proliferating cells, and the presence of DNA damage repair mechanisms limits the efficacy of these therapies, resulting in resistance to chemotherapy or radiation agents sex.
  • ATR increasing replication stress and increasing DNA damage, it can enhance the sensitivity of tumor cells to these DNA damage-induced therapies, help to overcome the drug resistance caused by radiotherapy or chemotherapy drugs due to damage repair, and can be used for gene therapy
  • the dose of chemotherapy or radiotherapy should be reduced, thereby reducing the toxicity to the blood and gastrointestinal organ systems.
  • ATR inhibitors can be used to increase replication stress and induce tumor cell death. Indeed, studies have revealed that ATR inhibitors are synthetically lethal against p53-mutant tumors or tumors that have lost ATM function and are synergistic when combined with a variety of replication stress/DNA damage-inducing chemotherapeutic agents, such as platinum, ionizing radiation and PARP inhibitors.
  • ATR inhibition can also prevent the occurrence of cancer, because ATR is also an important member of the DNA damage checkpoint, and ATR inhibition will limit the expansion of original cancer cells caused by oncogene activation.
  • ATR inhibitors have been developed (eg WO2017202748, CN111848605A, WO2020087170, WO2020049017). However, it is still very challenging to develop new potent ATR inhibitors.
  • the high identity of the PIKK kinase family to related lipid kinases such as phosphatidylinositol 3-kinase (PI3KS) as well as mTOR increases the risk of inhibition of other kinases, which may increase toxicity or counteract the therapeutic effect of ATR inhibition; in addition, some ATR
  • the application of inhibitors is also limited by physicochemical properties, pharmacokinetic properties, and drug-drug interactions.
  • the present inventors have identified through research that the compounds of the present invention exhibit satisfactory ATR inhibitory activity, and show good performance in in vivo and/or in vitro pharmacokinetic experiments, indicating improved druggability and improved bioavailability Spend. Therefore, the compound of the present invention can not only achieve the purpose of preventing or treating diseases related to ATR, but also the prepared medicine is expected to have improved absorption, improved curative effect at the same dose, or provide the same curative effect at a lower dose and/or Reduce possible side effects.
  • the present invention also provides the use of the compound of the present invention in the preparation of a medicament for the prevention or treatment of diseases associated with ATR, the pharmaceutical composition comprising the compound, and the prevention and/or treatment of ATR-related diseases by administering the compound. way of disease.
  • compounds of the formula (I) of the present invention are provided, their stereoisomers, mutuals, which have ATR inhibitory activity and are used as medicines, especially as ATR inhibitors for the treatment or prevention of ATR-related diseases.
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may additionally comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the invention.
  • a pharmaceutical combination such as a kit, comprising a compound of the invention and a further active agent.
  • the use of the compound of the present invention or a pharmaceutical composition comprising it for preventing or treating ATR-related diseases in mammals, especially humans.
  • a method of inhibiting ATR in vivo or in vitro comprising contacting said ATR with an effective amount of a compound of the invention.
  • a method for preventing or treating an ATR-related disease in an individual comprising administering an effective amount of the compound of the present invention described herein or a medicament comprising it combination.
  • treating means administering one or more compounds of the invention described herein to a subject, such as a mammal, such as a human, suffering from, or having symptoms of, the disease, for Curing, alleviating, alleviating or affecting the disease or the symptoms of the disease.
  • a subject such as a mammal, such as a human
  • said disease is an ATR-associated disease as defined below, especially a tumor or cancer.
  • prophylaxis as used herein is well known in the art and is administered to a subject, such as a mammal, such as a human, suspected of suffering from or susceptible to an ATR-associated disease as defined herein, especially cancer or tumor
  • a subject such as a mammal, such as a human
  • ATR-associated disease as defined herein, especially cancer or tumor
  • One or more of the compounds of the invention described herein results in a reduced risk of developing a defined disease.
  • prevention encompasses the use of the compounds of the invention prior to the diagnosis or determination of any clinical and/or pathological symptoms.
  • inhibitor and “reduce” or any variation of these terms, as used herein, refer to the ability of a biologically active agent to reduce the signaling activity of a target of interest by interacting directly or indirectly with the target, and refer to Any measurable reduction or complete inhibition of the activity of a target of interest.
  • the activity e.g., ATR activity
  • the activity may be reduced by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% compared to normal conditions. %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therein.
  • selective inhibition refers to the ability of a bioactive agent to preferentially reduce signaling activity of a target of interest over off-target signaling activity by interacting directly or indirectly with the target. As far as the compound of the present invention is concerned, it can selectively inhibit the activity of ATR, thereby reducing Simultaneously acting on other kinases may cause toxicity or offset the inhibitory effect of ATR.
  • the present invention has at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% ATR as compared to another specific kinase , 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range of better activity derivable therein, or with another At least 1-, 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-, or 500-fold better activity on ATR than the activity of a particular kinase.
  • cancer refers to neoplastic cell growth and proliferation, whether malignant or benign, and to all precancerous and cancerous cells and tissues.
  • the cancer or tumor includes but not limited to colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma Carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, lung cancer, leukemia, bladder cancer, stomach cancer, cervical cancer, testicular cancer, skin cancer, rectal cancer, thyroid cancer, kidney cancer, uterine cancer, pemphigus cancer, liver cancer, auditory nerve tumor, oligodendroglioma, meningioma, neuroblastoma, eye cancer.
  • an "anticancer effect” or “antitumor effect” as described herein includes, but is not limited to, effects on response rate, time to disease progression, and survival rate.
  • the antitumor effects of the compounds of the present invention and their medical uses and methods include, but are not limited to, inhibiting tumor growth, delaying tumor growth, regressing tumors, shrinking tumors, prolonging tumor regrowth after cessation of treatment, slowing down disease progression, and also including preventing tumorigenesis .
  • the term "therapeutically effective amount” means an amount sufficient to alleviate or completely relieve the symptoms or other deleterious effects of a disorder; reverse, completely stop or slow the progression of a disorder; or reduce the risk of a worsening of a disorder when administered to an individual to treat a disease.
  • the “effective amount” may vary depending on the compound, the disease and its severity, and the age, weight, etc. of the individual to be treated.
  • the term "individual” as used herein includes a human or a non-human animal.
  • exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • ATR-associated disease refers to a disease in which ATR activity promotes the occurrence and development of the disease, or inhibition of ATR will reduce the incidence of the disease, reduce or eliminate the disease symptoms.
  • ATR-associated disease preferably refers to an ATR-mediated disease, more preferably cancer or tumor.
  • ATR kinase inhibitors should be of therapeutic or prophylactic value for hematological malignancies such as leukemia (including chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia), Multiple myeloma, lymphoid malignancies (such as lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma), myelodysplastic syndromes, and solid tumors such as carcinomas and sarcomas and their metastases, such as breast cancer, Lung cancer (non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma, bronchoalveolar carcinoma), central nervous system tumors (eg, glioma, dysembryonic dysplastic neuroepithelial tumor, glioblastoma multiforme, mixed Glioma, medulloblastoma, retinoblastom
  • the compounds of the present invention are especially useful for the treatment of patients with lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, renal cancer, gastric cancer, sarcoma, head and neck cancer, central nervous system tumors and their metastases, and patients with Patients with acute myeloid leukemia.
  • composition or “pharmaceutical preparation” as used herein refers to a compound comprising one or more compounds of formula (I) of the present invention or its stereoisomers, tautomers, stable isotope derivatives, pharmaceutically
  • composition of acceptable salt or solvate and pharmaceutically acceptable excipient or carrier generally accepted in the art, and may be in solid, semi-solid, liquid or gaseous form.
  • the term "pharmaceutical combination" as used herein means that the compounds of the present invention may be combined with other active agents for the purposes of the present invention.
  • the other active agent may be one or more additional compounds of the invention, or may be a second or additional (e.g. a third) compound which is compatible with the compounds of the invention, i.e. does not adversely affect each other, or has complementary activities. ) compound.
  • Such active agents are suitably present in combination in amounts effective to achieve the intended purpose.
  • the other active agent may be co-administered with the compound of the present invention in a single pharmaceutical composition, or administered separately from the compound of the present invention in separate discrete units, eg, in kit form, which when administered separately may be carried out simultaneously or sequentially. The sequential administration may be close or distant in time.
  • the term "pharmaceutically acceptable” means approved or may be approved by the corresponding agency of each country, or listed in the generally accepted pharmacopoeia for use in animals, and more particularly in humans, or when administered in appropriate amounts to animals, such as humans. Molecular entities and compositions that do not produce adverse, allergic or other untoward reactions.
  • the term "pharmaceutically acceptable excipient or carrier” means one or more compatible solid or liquid filler or gel substances, which are pharmacologically inactive, compatible with the other ingredients in the composition and should be acceptable for administration to warm-blooded animals such as humans, for use as carriers or vehicles in administration forms for the compounds of the present invention, examples of which include, but are not limited to, cellulose and its derivatives (such as carboxymethylcellulose Sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as magnesium stearate), calcium sulfate, vegetable oil, polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween category), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, etc.
  • cellulose and its derivatives such as carboxymethylcellulose Sodium, cellulose acetate
  • the term "pharmaceutically acceptable salt” means a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and may be inorganic acid addition salts or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids, the Organic acids such as acetic, propionic, caproic, glycolic, pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, almond acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptanoic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butyl Acetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid,
  • stereoisomer refers to an isomer formed by at least one asymmetric center. In compounds having one or more, for example 1, 2, 3 or 4, asymmetric centers, racemic mixtures, single enantiomers, diastereomers and individual diastereomers may arise Construct. Certain molecules may also exist as geometric isomers (cis/trans). Compounds of the invention may also exist as mixtures of two or more structurally distinct forms in rapid equilibrium, commonly referred to as tautomers, representative examples include keto-enol, phenol-keto, nitroso- Oxime tautomers, etc. It should be understood that the scope of the present invention covers all such isomers and mixtures thereof in any proportion, such as 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97% , 98%, 99%.
  • solvate refers to solvent addition forms containing stoichiometric or non-stoichiometric amounts of solvent, including any solvated form of the compounds of the invention, including for example solvates with water, such as hydrates, Or a solvate with an organic solvent, such as methanol, ethanol or acetonitrile, ie as methanolate, ethanolate or acetonitrile, respectively; or in any polymorphic form. It should be understood that such solvates of the compounds of the invention also include solvates of the pharmaceutically acceptable salts of the compounds of the invention.
  • prodrug means a compound having a cleavable group and becoming a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions.
  • Prodrugs include acid derivatives well known in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine, or anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acid groups pendant on the compounds of the invention are particularly useful prodrugs. Specific such prodrugs are C 1-8 alkyl, C 2-8 alkenyl, optionally substituted C 6-10 aryl and (C 6- 10 aryl)-(C 1- 4 alkyl) esters.
  • isotopic variation refers to a compound that contains unnatural proportions of isotopes at one or more atoms that make up the compound.
  • Compounds of the present invention are those that contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds, resulting in isotopic variations, whether radioactive or not, that are intended to be encompassed within the scope of the present invention.
  • isotopes that may be incorporated into the compounds of the present invention, and pharmaceutically acceptable salts thereof, include, but are not limited to, isotopes of hydrogen (e.g., 2H, 3H); isotopes of carbon (e.g., 11C, 13C, and 14C); isotopes of chlorine (such as 36Cl); isotopes of fluorine (such as 18F); isotopes of iodine (such as 123I and 125I); isotopes of nitrogen (such as 13N and 15N); isotopes of oxygen (such as 15O, 17O and 18O); 32P); and sulfur isotopes (eg 35S).
  • isotopic variations of the compounds of the invention may generally be prepared by conventional methods using the appropriate isotopic variation of suitable reagents.
  • compound structural formula herein Represents an aromatic ring, that is, the selection of A 1 to A 5 makes the formed ring satisfy the valence bond theory of an aromatic ring, and is chemically feasible and stable.
  • the structure fragments used in this article The bond indicated to cross it is the bond by which the structural fragment connects to the rest of the molecule.
  • halo or halogen as used herein means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Preferred halo is fluorine or chlorine.
  • halogen-substituted groups is intended to include monohalogenated or polyhalogenated groups in which one or more (eg 2, 3, 4, 5 or 6) identical or different halogen substituents One or more (eg 2, 3, 4, 5 or 6) hydrogens in a group.
  • cyano as used herein means the group -CN.
  • hydroxyl refers to -OH.
  • alkyl refers to a linear or branched saturated hydrocarbon group composed of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1-10, such as 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
  • C 1 -C 6 alkyl refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, examples of which are methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, etc.
  • Certain alkyl groups have 1 to 3 carbon atoms.
  • alkoxy means the group -O-alkyl, wherein alkyl has the meaning described herein.
  • the term includes the group -OC 1-6 alkyl, more specifically -OC 1-3 alkyl.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy, isopropoxy), butoxy (including n-butoxy, isobutoxy, tert-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy, neopentyloxy), hexyloxy (including n-hexyloxy, isohexyloxy) and the like.
  • Certain alkoxy groups have 1 to 3 carbon atoms.
  • alkylene used herein alone or in combination with other groups refers to a saturated straight-chain or straight-chain divalent hydrocarbon group.
  • C 1-3 alkylene refers to an alkylene group having 1 to 3 carbon atoms, such as methylene, ethylene, propylene, 1-methylethylene, 2-methyl Ethylene, etc.
  • cycloalkyl refers to a monocyclic, fused polycyclic, bridged polycyclic or spiro non-aromatic saturated monovalent hydrocarbon ring structure having the indicated number of ring atoms.
  • Cycloalkyl can have from 3 to 12 carbon atoms (i.e. C 3 -C 12 cycloalkyl), such as C 3-10 cycloalkyl, C 3-8 cycloalkyl, C 3-6 cycloalkyl, C 5 -6 cycloalkyl.
  • Suitable cycloalkyl groups include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; or polycyclic (e.g., bicyclic) structures, including spiro Ring, fused or bridged systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, spiro[3.4]octyl, bicyclo[3.1.1]hexyl, bicyclo[3.1. 1] heptyl or bicyclo [3.2.1] octyl, etc.
  • monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl
  • polycyclic (e.g., bicyclic) structures including spir
  • aryl as used herein means a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom in an aromatic ring system. Specifically, aryl refers to a monocyclic or fused polycyclic aromatic ring structure having the indicated number of ring atoms. In particular, the term includes groups comprising 6 to 14, eg 6 to 10, preferably 6 ring members. Particular aryl groups include phenyl and naphthyl, the most specific aryl group being phenyl.
  • substituted or “substituted” means that one or more (eg, 1, 2, 3, or 4) hydrogens on the designated atom are replaced by the designated group, provided that it does not exceed Where the indicated atoms are bonded at their normal valences at the current situation and form stable compounds, combinations of substituents and variables are permissible only if such combinations form stable compounds.
  • the term "optionally substituted”, unless otherwise indicated, means that a group may be unsubstituted or replaced by one or more (eg 0, 1, 2, 3, 4 or 5 or more)
  • the listed substituents are substituted, wherein the substituents may be the same or different.
  • Cn-n+m or Cn - Cm in the definition of the compounds of the present invention includes various situations of n to n+m carbons, for example, C 1-6 includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 , including any range from n to n+m, for example, C 0-6 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 0- 1. C 0-2 , C 0-3 , C 0-4 , C 0-5 , C 1-2 , C 1-3 , C 1-4 , C 2-3 etc.
  • n-membered to n+m-membered in the definition of the compound of the present invention means that the number of ring atoms can be any one between n and n+m, and also includes any range of n-n+m-membered.
  • the stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates and prodrugs are as described above in the Definitions section.
  • the compound of the present invention is a free form of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; most preferably a free form of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Certain compounds of the present invention may exist in polymorphic or amorphous forms which are also within the scope of the present invention.
  • the compound of formula (I) may be in the form of a co-crystal with another chemical entity, and this description includes all such co-crystals.
  • the compounds of the invention may exist as individual enantiomers or as mixtures of enantiomers, and those skilled in the art will be able to determine which isomeric forms of the compounds of the invention are stable and feasible.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof which is an enantiomeric excess (%ee) >95, >98% or >99% of a single enantiomer.
  • the single enantiomer is present in >99% enantiomeric excess (%ee).
  • the compounds of the invention also encompass possible N-oxides, and those skilled in the art will be able to determine stable and viable N-oxides of the compounds of the invention.
  • the compounds of the present invention also encompass metabolites of the compounds of the present invention, that is, substances formed in vivo by oxidation, reduction, hydrolysis, amidation, esterification, etc. when the compounds of the present invention are administered, which can be identified by techniques known in the art.
  • the present invention provides a compound of formula (I), its stereoisomer, tautomer, stable isotope variant, pharmaceutically acceptable salt or solvate:
  • a 1 , A 2 and A 5 are each independently C or N;
  • a 3 and A 4 are each independently CR 4 , N or NR 5 ;
  • X is O, C(R6 )2 or NR7 ;
  • Y is N or CR 8 ;
  • R 1 , R 2 and R 3 are each independently H, -OH, oxo, halogen, CN, -C 1-6 alkyl or -OC 1-6 alkyl, wherein the C 1-6 alkyl is optionally Substituted by one or more halogens or hydroxy groups; or R 1 and R 2 are joined together to form a C 1-3 alkylene bridge;
  • R 4 is H, oxo, halogen or -C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by one or more halogen or hydroxyl;
  • R 5 is H or -C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by one or more halogens;
  • R 6 are each independently H, halogen, CN, -OH, -NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alkyl) 2 , -C 1-6 alkyl, - OC 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)-C 3-6 cycloalkyl, -SO 2 -C 1-6 alkyl, -SO 2 -C 3-6 cycloalkyl, -SO-C 1-6 alkyl , -SO-C 3-6 cycloalkyl, C 6-10 aryl or C 3-6 cycloalkyl, where -C 1-6 Alkyl, C 6-10 aryl or C 3-6 cycloalkyl are optionally substituted by one or more halogen, hydroxy, -OC 1-6 alkyl, -C 1-6 alkyl, or halogen or hydroxy C 1-6 alkyl substitution;
  • R 7 is H, -C 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)-C 3-6 cycloalkyl, -SO 2 -C 1-6 alkyl , -SO 2 -C 3-6 cycloalkyl, -SO-C 1-6 alkyl or -SO-C 3-6 cycloalkyl, wherein -C 1-6 alkyl or C 3-6 cycloalkane
  • the group is optionally substituted by one or more halogen, hydroxyl, -OC 1-6 alkyl, -C 1-6 alkyl, or halogen or hydroxy substituted C 1-6 alkyl;
  • R 8 is H, -OH or halogen
  • n and m are each independently an integer of 0 to 4.
  • At least two of A 1 , A 2 , A 3 , A 4 and A 5 are N or NR 5 and the remainder are C or CR 4 ; preferably two of them are N or NR 5 , the rest are C or CR 4 .
  • the six- to five-membered heteroaryl moiety comprising A 1 to A 5 has a structure selected from:
  • the six-membered and five-membered heteroaryl moiety comprising A 1 to A 5 is selected from:
  • the six-membered and five-membered heteroaryl moiety comprising A 1 to A 5 is preferably
  • the six-membered and five-membered heteroaryl moiety comprising A 1 to A 5 is preferably
  • the six-membered and five-membered heteroaryl moiety comprising A 1 to A 5 is preferably
  • the six-membered and five-membered heteroaryl moiety comprising A 1 to A 5 is preferably
  • R4 is H.
  • R4 is oxo or halo.
  • R 4 is -C 1-6 alkyl, optionally substituted by one or more halogen or hydroxy; such as but not limited to methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-Methylpentyl, -CH 2 F, -CHF 2 , -CF 3 , -C 2 F 5 , -CH 2 CF 3 , -CH 2 Cl, -CH 2 CH 2 CF 3 , -CH(CF 3 ) 2 , —CH 2 OH or —CH 2 CH 2 OH.
  • R 4 is -C 1-3 alkyl, eg methyl, ethyl
  • R4 is preferably H.
  • R 5 is H.
  • R 5 is -C 1-6 alkyl, optionally substituted by one or more halogens; such as but not limited to methyl, ethyl, propyl (including n-propyl base and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2- Methylpentyl, -CH 2 F, -CHF 2 , -CF 3 , -C 2 F 5 , -CH 2 CF 3 , -CH 2 Cl, -CH 2 CH 2 CF 3 or -CH(CF 3 ) 2 .
  • halogens such as but not limited to methyl, ethyl, propyl (including n-propyl base and isopropyl), butyl (including n-butyl, iso
  • R 5 is preferably C 1-3 alkyl, such as methyl, ethyl, propyl, isopropyl, most preferably methyl.
  • X is O.
  • X is C(R 6 ) 2 , wherein each R 6 is H.
  • X is C(R 6 ) 2 , wherein one of R 6 is H and the other is selected from halogen, CN, -OH, -C 1-6 alkyl, - OC 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)-C 3-6 cycloalkyl, -SO 2 -C 1-6 alkyl, -SO 2 -C 3- 6 cycloalkyl, -SO-C 1-6 alkyl, -SO-C 3-6 cycloalkyl, C 6-10 aryl or C 3-6 cycloalkyl, where -C 1-6 Alkyl, C 6-10 aryl or C 3-6 cycloalkyl are optionally substituted by one or more halogen, hydroxy, -OC 1-6 alkyl, -C 1-6 alkyl, or halogen or hydroxy -C 1-6 alkyl substitution.
  • X is C(R 6 ) 2 , wherein one of R 6 is H and the other is selected from halogen such as fluorine, chlorine, bromine, iodine.
  • X is C(R 6 ) 2 , wherein one of R 6 is H and the other is OH, CN, NH 2 , -NH-C 1-6 alkyl, -N(C 1-6 alkyl) 2 , such as but not limited to OH, CN, -NH 2 , -NH-CH 3 , -NH-CH 2 -CH 3 , -N(CH 3 ) 2 , -N( CH 2 -CH 3 ) 2 , -N(CH 3 )(CH 2 -CH 3 ).
  • X is C(R 6 ) 2 , wherein one of R 6 is H and the other is -C 1-6 alkyl, optionally replaced by one or more halogen , hydroxyl or -OC 1-6 alkyl substitution, such as but not limited to methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, -CH 2 F, -CHF 2 , -CF 3 , -C 2 F 5.
  • R 6 is H and the other is -C 1-6 alkyl, optionally replaced by one or more halogen , hydroxyl or -OC 1-6 alkyl substitution, such as but not limited to methyl, ethyl, propy
  • X is C(R 6 ) 2 , wherein one of R 6 is H, and the other is -OC 1-6 alkyl, wherein -C 1-6 alkyl Optionally substituted with one or more halogen, hydroxy, or -OC 1-6 alkyl, such as but not limited to -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -OCH 2 CF 3 , -OCH 2 CH 2 OH , -OCH2CH2OCH3 .
  • X is C(R 6 ) 2 , wherein one of R 6 is H and the other is -C(O)-C 1-6 alkyl, -C(O )-C 3-6 cycloalkyl, -SO 2 -C 1-6 alkyl, -SO 2 -C 3-6 cycloalkyl, -SO-C 1-6 alkyl, -SO-C 3-6 Cycloalkyl, C 6-10 aryl or C 3-6 cycloalkyl, such as but not limited to -C(O)-CH 3 , -C(O)-CH 2 CH 3 , C(O)-CH 2 CH 2 CH 3 , -C(O)-CH(CH 3 ) 2 , -C(O)-cyclopropyl, -C(O)-cyclopentyl, -C(O)-cyclohexyl, -SO 2 -CH 3 , -SO 2 -CH 2 CH
  • X is C(R 6 ) 2 , wherein each R 6 is independently -C 1-6 alkyl, halogen, CN, -OH, -NH 2 , -NH -C 1-6 alkyl, -N(C 1-6 alkyl) 2 , -OC 1-6 alkyl, wherein -C 1-6 alkyl is optionally replaced by one or more halogen, hydroxyl or - OC 1-6 alkyl substitution;
  • R 6 are halogen at the same time, C 1-6 alkyl optionally substituted by (such as halogen) at the same time, one is halogen and the other is said optionally substituted by (such as halogen) C 1-6 alkyl, one is OH or -OC 1-6 alkyl and the other is said C 1-6 alkyl optionally substituted by (eg halogen), one is NH 2 , -NH-C 1-6 alkyl or -N(C 1-6 alkyl) 2 and the other is said optionally substituted (eg halogen) C 1-6 alkyl, one is CN and the other is said optionally C 1-6 alkyl substituted by (eg halogen);
  • X is for example but not limited to CF 2 , CCl 2 , CBr 2 , CFCl, C(CH 3 ) 2 , C(CH 2 CH 3 ) 2 , C(CH 3 )(CH 2 CH 3 ), C(CF 3 )( CF 3 ), C(CH 3 )(CF 3 ), C(CH 3 )(CH 2 OH), C(CH 3 )(CH 2 OCH 3 ), C(CH 3 )(F), C(CH 3 )(OCH 3 ), C(CH 3 )(OH), C(CH 3 )(NH 2 ), -C(CH 3 )(NHCH 3 )-.
  • X is C(R 6 ) 2 , wherein each R 6 is independently selected from H or halogen, for example both are H, or both are halogen, for example both are F.
  • X is NR7 and R7 is H.
  • X is NR 7
  • R 7 is -C 1-6 alkyl, optionally substituted by one or more halogen, hydroxy, or -OC 1-6 alkyl,
  • X is NR 7
  • R 7 is -C(O)-C 1-6 alkyl, -C(O)-C 3-6 cycloalkyl, -SO 2 -C 1-6 alkyl, -SO 2 -C 3-6 cycloalkyl, -SO-C 1-6 alkyl or -SO-C 3-6 cycloalkyl, such as but not limited to -C(O )-CH 3 , -C(O)-CH 2 CH 3 , C(O)-CH 2 CH 2 CH 3 , -C(O)-CH(CH 3 ) 2 , -C(O)-cyclopropyl , -C(O)-cyclobutyl, -C(O)-cyclopentyl, -C(O)-cyclohexyl, -SO 2 -CH 3 , -SO 2 -CH 2 CH 3 , SO 2 -CH 2 CH 2 CH 3
  • X is NR 7 , R 7 is selected from H, -C 1-6 alkyl and -C(O)-C 1-6 alkyl, preferably -C 1- 6 alkyl, or preferably -C(O)-C 1-6 alkyl, such as but not limited to methyl, ethyl, propyl, isopropyl, -C(O)-CH 3 , -C(O) -CH2CH3, C(O ) -CH2CH2CH3 or -C (O)-CH ( CH3 ) 2 .
  • X is preferably -O-, -NH-, -N(C 1-6 alkyl)-, -CH 2 -, -C(halogen) 2 -, for example - O-, -NH-, -N(CH 3 )-, -CH 2 -, -C(F) 2 -.
  • X is preferably -O-, -N(C 1-6 alkyl)-, -N(CO-C 1-6 alkyl)-, -CH 2 -, -CH(C 1-6 alkyl)-, -C(C 1-6 alkyl) 2 - or -C(halogen) 2 -, for example -O-, -N(CH 3 )-, -N(CO -CH 3 )-, -CH 2 -, -C(F) 2 -.
  • Y is N.
  • Y is CR8 , wherein R8 is H.
  • Y is CR8 , wherein R8 is OH.
  • Y is CR 8 , wherein R 8 is halogen, eg fluorine, chlorine, bromine, iodine, preferably F.
  • Y is preferably N, or CR8 , wherein R8 is OH; more preferably Y is N.
  • the six-membered ring comprising X and Y selected from Preferably the six membered ring comprising X and Y is selected from More preferably the six membered ring comprising X and Y is selected from R 6 , R 7 and R 8 respectively have the meanings defined in each of the corresponding embodiments above, preferably R 6 is selected from H, halogen and C 1-6 alkyl, R 7 is selected from C 1-6 alkyl and -CO- C 1-6 alkyl.
  • R 1 and R 2 are each independently H.
  • R and R are each independently -OH , oxo, halogen, CN, -C 1-6 alkyl or -OC 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogen or hydroxyl, such as but not limited to -OH, oxo, fluorine, chlorine, bromine, iodine, CN, -CH 3 , -CH 2 CH 3 , -O -CH 3 , -O-CH 2 CH 3 , -CF 3 , -CH 2 CF 3 , -CH 2 OH, -CH 2 CH 2 OH, preferably -CH 3 , -CF 3 or -CH 2 CH 3 , most -CH3 is preferred.
  • R 1 and R 2 are joined together to form a C 1-3 alkylene bridge, eg -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -.
  • R 1 and R 2 are connected together to form a C 1-3 alkylene bridge, such as but not limited to:
  • Y is N and X is O.
  • R 1 and R 2 are each independently H, -CH 3 , -CH 2 CH 3 , or R 1 and R 2 are linked together to form a C 1-3 alkylene A base bridge, preferably a C 2 ethylene bridge.
  • m and n are both zero.
  • one of m and n is 0 and the other is 1, at this time R 1 or R 2 is not hydrogen, and may be attached to the ortho position of Y or X on the ring
  • the ortho position is preferably connected to the ortho position of Y.
  • R 1 or R 2 is C 1-6 alkyl, such as but not limited to -CH 3 , -CH 2 CH 3 or -CH(CH 3 ) 2 , preferably R 1 or R 2 is -CH 3 , attached to
  • the ortho-position of Y or the ortho-position of X is preferably connected to the ortho-position of Y.
  • R 1 or R 2 is not hydrogen, and can be connected to the ortho position of Y, X on the ring at the same time
  • R 1 or R 2 are each independently C 1-6 alkyl, such as but not limited to -CH 3 , -CH 2 CH 3 or -CH 2 -CH 2 -CH 3 , preferably R 1 or R 2 is - CH 3 , which is connected to the adjacent position of Y at the same time.
  • one of m and n is 0, the other is 3 or 4, at this time R 1 or R 2 is not hydrogen, the R 1 or R 2 are for example but not limited to - CH 3 , -CH 2 CH 3 or -CH 2 -CH 2 -CH 3 , for example, R 1 or R 2 is C 1-6 alkyl, preferably R 1 or R 2 is -CH 3 .
  • m and n are both 1 , at this time R and R are not hydrogen , each independently can be connected to the ortho position of Y or the ortho position of X on the ring, for example Both are connected to the ortho position of Y, or are connected to the ortho position of X, or are respectively connected to the ortho position of Y and the ortho position of X ; preferably R and R are C 1-6 alkyl , more preferably R and R 2 is -CH 3 , both are connected to the ortho-position of Y, or both are connected to the ortho-position of X, or are respectively connected to the ortho-position of Y and the ortho-position of X.
  • m and n are both 1 , at this time R and R are not hydrogen , and are connected to, preferably simultaneously connected to, R and R at the ortho - position of Y and the ortho-position of X 2 are linked together to form a C 1-3 alkylene bridge, eg -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -.
  • m is 1 and n is 2, or m is 1 and n is 3, or m is 1 and n is 4, or m is 2 and n is 2, or m is 2 and n is 3, or m is 2 and n is 4, or m is 3 and n is 4, or m is 4 and n is 4 , wherein for example R and R are C 1-6 alkyl , preferably R 1 and R 2 are -CH 3 .
  • one of m and n is 0, the other is 1, R 1 or R 2 are each independently C 1-6 alkyl, optionally replaced by one or more halogen Substituted, connected to the ortho-position of Y or the ortho-position of X;
  • R 1 or R 2 are each independently C 1-6 alkyl, optionally substituted by one or more halogens, connected to the ortho position of Y, ortho to X or the adjacent positions connected to X and Y respectively;
  • m and n are both 1 and R 1 and R 2 are each independently C 1-6 alkyl, optionally substituted by one or more halogens, both are connected to the ortho position of Y on the ring, and both are connected to the ortho position of X bit, or respectively connected to the ortho-position of Y and the ortho-position of X.
  • one of m and n is 0, the other is 1, R 1 or R 2 is C 1-6 alkyl, and is connected to the ortho position of Y or to the ortho.
  • one of m and n is 0, the other is 1, R 1 or R 2 is C 1-6 alkyl, optionally substituted by halogen, and is attached to Y Ortho position; or one of m and n is 0, the other is 2, R 1 or R 2 are each independently C 1-6 alkyl, optionally substituted by halogen, all connected to the ortho position of Y.
  • R and/or R may be in R or S configuration, preferably R configuration, where chemically feasible.
  • R3 is H.
  • R3 is halogen, such as fluorine, chlorine, bromine, iodine, preferably fluorine or chlorine.
  • the compound of the present invention covers each of the above independent embodiments or each of the specific exemplified embodiments, and also encompasses any combination or subcombination of the above-mentioned individual embodiments or specific exemplified embodiments, and also covers the above Any combination of any preferred or exemplary embodiments constitutes an embodiment.
  • the six-membered and five-membered heteroaryl moiety comprising A 1 to A 5 is selected from:
  • the six-membered ring comprising X and Y is selected from
  • R 1 and R 2 are each independently H or -C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted by one or more halogens; or R 1 and R 2 are linked together to form C 1- 3 alkylene bridges;
  • R 3 is H or halogen
  • R4 is H ;
  • R 5 is H or -C 1-6 alkyl
  • R 6 are each independently H, halogen, -C 1-6 alkyl or -OC 1-6 alkyl, wherein -C 1-6 alkyl is optionally substituted by one or more halogens;
  • R 7 is H or -C 1-6 alkyl, wherein -C 1-6 alkyl is optionally substituted by one or more halogens;
  • R 8 is H, -OH or halogen
  • n and m are each independently an integer of 0 to 2.
  • the six- and five-membered heteroaryl moieties comprising A 1 to A 5 are selected from
  • the six membered ring comprising X and Y is selected from
  • the six membered ring comprising X and Y is
  • a six-membered ring containing X and Y is wherein R 1 is each independently C 1-6 alkyl, optionally substituted by halogen, n is selected from 0, 1 or 2; or a six-membered ring comprising X and Y R 1 and R 2 are joined together to form a C 1-3 alkylene bridge, e.g.
  • the six membered ring comprising X and Y is for example a six-membered ring containing X and Y is Wherein R 1 is each independently C 1-6 alkyl, optionally substituted by halogen, n is selected from 1 or 2, R 7 is selected from C 1-6 alkyl or -CO-C 1-6 alkyl.
  • the six membered ring comprising X and Y is for example a six-membered ring containing X and Y is Wherein R 1 is each independently C 1-6 alkyl, optionally substituted by halogen, n is selected from 0 or 1, R 6 is selected from H, halogen or C 1-6 alkyl substituted by halogen.
  • the six membered ring comprising X and Y is selected from
  • the six membered ring comprising X and Y is selected from
  • R and R are each independently H.
  • R 1 and R 2 are each independently -C 1-6 alkyl, optionally substituted with one or more halogens, for example -CH 3 , -CH 2 CH 3 , -CH 3 , -CH 2 CH 3 , - CH2CH2CH3 , -CH ( CH3 )2 , -CF3 or -CH2CF3 , most preferably -CH3 .
  • R 1 and R 2 are joined together to form a C 1-3 alkylene bridge, preferably a C 2 alkylene bridge.
  • R3 is H.
  • R 5 is -C 1-6 alkyl, for example -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , most -CH3 is preferred.
  • each R6 is independently H or halogen, preferably H or F.
  • R 7 is H, or -C 1-6 alkyl, eg -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , most preferably -CH3 .
  • R8 is -OH.
  • one of n and m is 0 and the other is 1
  • R or R is attached to the ortho position of Y or the ortho position of X on the ring, preferably attached to the ortho position of Y
  • R 1 or R 2 is C 1-6 alkyl, preferably R 1 or R 2 is -CH 3 , connected to the ortho position of Y or the ortho position of X, preferably connected to the ortho position of Y.
  • R 1 or R 2 are simultaneously connected to the ortho-position of Y, the ortho-position of X, or respectively connected to the ortho-position of Y on the ring.
  • the ortho-position and the ortho-position of X are preferably connected to the ortho-position of Y at the same time.
  • R 1 or R 2 is C 1-6 alkyl, preferably R 1 or R 2 is -CH 3 , and is connected to the ortho position of Y at the same time.
  • both n and m are 1 , and each of R and R can be independently connected to the ortho position of Y on the ring, or the ortho position of X, for example, both are connected to the ortho position of Y.
  • R1 and R2 are C 1-6 alkyl , more preferably R 1 and R 2 are -CH 3 , both are connected to the ortho-position of Y, or both are connected to the ortho-position of X, or are respectively connected to the ortho-position of Y and the ortho-position of X, preferably both are connected to the ortho-position of Y;
  • R 1 and R 2 connected to, preferably simultaneously connected to, the Y ortho position and the X ortho position are linked together to form a C 1-3 alkylene bridge, such as -CH 2 -, -CH 2 CH 2 -, -CH 2 CH2CH2- .
  • R and/or R may be in the R or S configuration, preferably the R configuration, where chemically feasible.
  • Specific embodiments of the compounds of the present invention include the following specific compounds, their stereoisomers, tautomers, stable isotopic variants, pharmaceutically acceptable salts or solvates,
  • each preferred embodiment of the compound of formula (I) as defined herein is preferred, more preferably the Specific compounds listed.
  • ATR kinase is known to play a role in tumorigenesis as well as in a variety of other diseases.
  • the above-mentioned compounds of formula (I) are capable of potently inhibiting ATR kinase and thus have utility as anti-proliferative, apoptotic and/or anti-invasive drugs in the suppression and/or treatment of solid and/or liquid tumor diseases value.
  • the compounds of the present invention are expected to be useful in the prophylaxis or treatment of those tumors which are sensitive to inhibition of ATR.
  • the compounds of the present invention are expected to be useful in the prophylaxis or treatment of those tumors which are mediated solely or in part by ATR.
  • the compounds of the present invention can effectively inhibit the activity of ATR kinase and tumor cell lines, and can achieve one or more of the following technical effects:
  • IC50 is in the range of 0.1nM ⁇ 1 ⁇ M, preferably in the range of 0.1nM ⁇ 0.5 ⁇ M, preferably in the range of 0.1nM ⁇ 0.1 ⁇ M, more preferably in the range of 0.1nM ⁇ 50nM, 0.1 nM ⁇ 20nM, as verified in Activity Example 1; and/or
  • ⁇ Has good pharmacokinetic properties, such as longer t 1/2 , so that, for example, the dosing interval can be increased, and the half-life can be longer, so that patients have better compliance, as verified in Example 3 ;and / or
  • Good safety profile such as membrane permeability, P450 (reduced risk of drug interaction), lower toxicity and/or fewer side effects; and/or
  • the present invention also provides the following technical solutions in various aspects.
  • the invention provides compounds of the invention for use as a medicament, especially as an ATR inhibitor, more especially as an anticancer or antineoplastic agent.
  • the present invention provides compounds of the present invention for use in the treatment and/or prevention of ATR-associated diseases.
  • the present invention provides a method for treating and/or preventing ATR from promoting the occurrence and development of said disease, or inhibiting ATR will reduce the incidence of disease, reduce or eliminate disease symptoms.
  • Compounds, diseases such as tumors or cancers including but not limited to: hematological malignancies such as leukemia (including chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia and chronic myelogenous leukemia), multiple myeloma , malignancies of the lymphatic system (such as lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma), myelodysplastic syndromes, and solid tumors such as carcinomas and sarcomas and their metastases, such as breast cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma, bronchoalveolar carcinoma), central nervous system tumors (eg, glioma, dyse
  • the present invention provides a method for treating lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, kidney cancer, gastric cancer, sarcoma, head and neck cancer, central nervous system tumors and metastases thereof, and patients with A compound of formula (I), a stereoisomer, a tautomer, a stable isotopic variant, a pharmaceutically acceptable salt or a solvate thereof in a patient with acute myeloid leukemia.
  • the compounds of the invention may be formulated into pharmaceutical compositions according to standard pharmaceutical practice for therapeutic or prophylactic purposes.
  • drugs with better pharmacokinetic properties and higher bioavailability can be prepared from the compounds of the present invention.
  • the present invention provides a pharmaceutical composition comprising the above-mentioned compound of the present invention and a pharmaceutically acceptable excipient.
  • excipients to include in a particular composition will depend on factors such as the mode of administration and the form of the composition being provided. Suitable pharmaceutically acceptable excipients are well known to those skilled in the art and are described, for example, in Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.
  • diluents such as glucose, lactose or mannitol
  • carriers pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives additives, antioxidants, opacifiers, glidants, processing aids, coloring agents, flavoring agents, flavoring agents, and other known additives.
  • diluents such as glucose, lactose or mannitol
  • carriers pH adjusters, buffers, sweeteners, fillers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives additives, antioxidants, opacifiers, glidants, processing aids, coloring agents, flavoring agents, flavoring agents, and other known additives.
  • compositions of the present invention can be formulated by techniques known to those skilled in the art, such as those disclosed in Remington's Pharmaceutical Sciences 20th Edition.
  • compositions of the invention can be administered in standard manner.
  • suitable modes of administration include oral, intravenous, rectal, parenteral, topical, transdermal, ophthalmic, nasal, buccal or pulmonary (inhalation) administration, wherein parenteral infusions include intramuscular, intravenous, intraarterial, peritoneal Administered intradermally or subcutaneously.
  • the compounds of the present invention can be formulated by methods known in the art, for example as tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, Ointments, creams, drops, aerosols, dry powder preparations and sterile injectable aqueous or oily solutions or suspensions.
  • the size of the prophylactic or therapeutic dose of a compound of the invention will vary depending on a number of factors including the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician.
  • an effective amount is that amount sufficient to ameliorate or alleviate symptoms associated with the disease.
  • Such amounts may be administered as a single dose, or may be administered according to an effective treatment regimen.
  • the effective dose is about 0.0001 to about 5000 mg per kg body weight per day, for example about 0.01 to about 1000 mg/kg/day (single or divided administration).
  • the content or dosage of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, especially preferably 1-50 mg, Such as 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.; correspondingly, the pharmaceutical composition of the present invention will contain 0.05 to 99% w/w (percentage by weight), such as 0.05 to 80% w/w, such as 0.10 to 70% w/w, eg 0.10 to 50% w/w of the compound of the invention, all weight percentages being based on the total composition. It will be understood that it may be necessary to use dosages outside these limits in some cases.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and one or more pharmaceutically acceptable excipients, the composition being formulated for oral administration.
  • the composition may be presented in unit dosage form, for example in the form of a tablet, capsule or oral liquid formulation.
  • Such unit dosage forms may contain from 0.1 mg to 1 g, for example 5 mg to 250 mg, of a compound of the invention as active ingredient.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and one or more pharmaceutically acceptable excipients, the composition being formulated for topical administration.
  • Topical administration may be in the form of, for example, creams, lotions, ointments or transdermal patches, wherein the concentration of the compound of the invention may be from about 0.01 to 100 mg per gram of carrier.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and one or more pharmaceutically acceptable excipients, the composition being formulated for administration by inhalation.
  • Administration by inhalation can be by oral inhalation or intranasal administration.
  • the compounds of the present invention may be effectively used in the present invention in daily doses, for example up to 500 ⁇ g, such as 0.1-50 ⁇ g, 0.1-40 ⁇ g, 0.1-30 ⁇ g, 0.1-20 ⁇ g or 0.1-10 ⁇ g of the present invention compound.
  • compositions of the present invention for oral inhalation may be formulated as dry powders, suspensions (in liquids or gases) or solutions (in liquids), and may be in any suitable form and using any suitable inhaler device known in the art.
  • Administration including, for example, metered dose inhalers (MDIs), dry powder inhalers (DPIs), nebulizers, and soft mist inhalers.
  • MDIs metered dose inhalers
  • DPIs dry powder inhalers
  • nebulizers nebulizers
  • soft mist inhalers soft mist inhalers.
  • Multi-chambered devices can be used to deliver a compound of the present description and one or more other active ingredients, when present.
  • compositions of the invention may additionally comprise additional therapeutically active ingredients suitable for use in combination with the compounds of the invention.
  • therapeutically active ingredients suitable for administration in combination with the compounds of the present invention may be known anticancer drugs, especially other anticancer drugs related to DNA damage and repair mechanisms, including PARP inhibitors, HDAC inhibitors and the like.
  • Other therapeutically active ingredients suitable for administration in combination with the compounds of the present invention may also be selected from anticancer drugs related to cell division checkpoints, including ChK1/2 inhibitors, CDK4/6 inhibitors, ATM/ATR inhibitors.
  • Other known anticancer drugs that can be used in combination include alkylating agents, topoisomerase I/II inhibitors, RNA/DNA antimetabolites, antimitotic agents, antibody drugs, kinase inhibitors, and the like.
  • the compound of the invention and at least one known anticancer drug may be administered as a single pharmaceutical composition, or separately, simultaneously or sequentially as separate entities, eg, as a kit.
  • the compounds of the invention may also be administered as bioconjugates.
  • the bioconjugate is composed of the compound of the present invention and at least one known therapeutically active antibody such as Herceptin or MabThera, or growth factors such as EGF or FGF, or cytokines such as interleukin 2 or 4 or any cell surface Combined molecular composition.
  • the antibodies and other molecules function by delivering the compounds of the invention to their targets, while also enhancing the therapeutic activity of the antibodies or other molecules.
  • Compounds of the invention may also be used in combination therapy with radiation therapy, which may be administered at the same or different times.
  • the above-mentioned pharmaceutical composition provided by the present invention can be used for preventing or treating the above-defined ATR-related diseases in mammals such as human subjects.
  • the compounds of the present invention can be used in methods for treating ATR-related diseases in animals, especially mammals such as humans.
  • the present invention provides a method of modulating, especially inhibiting, the kinase activity of ATR, said method comprising contacting a cell with a compound of the invention as hereinbefore described to modulate, especially inhibit, the activity of ATR in the cell.
  • the present invention also correspondingly provides a method for inhibiting abnormal cell growth in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention, or a pharmaceutical composition comprising the compound of the present invention.
  • the present invention provides a method for preventing or treating a disease associated with ATR (for example, a disease that can be treated or prevented by ATR inhibition), the method comprising administering to an individual in need thereof an effective amount of the present invention as described above.
  • a compound of the invention or a pharmaceutical composition of the invention comprising the same.
  • the present invention provides the use of the compound of the present invention as described above or a pharmaceutical composition comprising it, for inhibiting ATR activity, or for treating and/or preventing diseases associated with ATR, for example by inhibiting ATR A disease that can be treated or prevented.
  • the present invention also provides the use of the above-mentioned compound of the present invention or the pharmaceutical composition containing it in the preparation of medicines, especially the use of medicines with ATR kinase inhibitor activity.
  • the present invention provides a compound of the present invention as described above or a pharmaceutical composition comprising it in the preparation of a medicament for treating or preventing a disease associated with ATR, for example a disease treatable or preventable by inhibition of ATR kinase Use, wherein said compound or pharmaceutical composition is optionally combined with one or more chemotherapy or immunotherapy.
  • the present invention also provides a method for preparing the compound of formula (I), and the general synthetic scheme for synthesizing the compound of the present invention is illustrated below.
  • suitable reaction conditions are known to the person skilled in the art or can be determined routinely.
  • the raw materials and reagents used in the preparation of these compounds are generally commercially available, or can be prepared by the methods below, methods similar to those given below, or methods known in the art.
  • Starting materials and intermediates in the synthetic reaction schemes can be isolated and purified, if necessary, by conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, and the like.
  • the materials can be characterized using conventional methods including physical constants and spectral data.
  • Step 1 heating the compound of formula (I-1) and amine in the presence of a base such as DIEA in a solvent such as NMP to obtain a compound of formula (I-2);
  • Step 2 reacting the compound of formula (I-2) with amine in the presence of a base such as DIEA and heating in a solvent such as NMP to obtain a compound of formula (I-3);
  • Step 3 reacting the compound of formula (I-3) with an iodination reagent such as NIS in a solvent such as ACN at room temperature to obtain the compound of formula (I-4);
  • Step 4 The compound of formula (I-4) is coupled by Suzuki, in the presence of a coupling agent such as Pd(dtbpf)Cl 2 /H 3 PO 4 , and heated in a solvent such as dioxane/water to obtain formula (I- 5) compounds; and
  • a coupling agent such as Pd(dtbpf)Cl 2 /H 3 PO 4
  • a solvent such as dioxane/water
  • Step 5 The compound of formula (I-5) is deprotected under the action of acid to obtain the compound of formula (I).
  • Step 1 the compound of formula (II-1) reacts with an iodination reagent such as NIS in the presence of an acid such as TFA in a solvent such as CHCl3 at room temperature to obtain a compound of formula (II-2);
  • an iodination reagent such as NIS
  • an acid such as TFA
  • a solvent such as CHCl3
  • Step 2 reacting the compound of formula (II-2) with amine in the presence of a base such as DIEA and heating in a solvent such as THF to obtain a compound of formula (II-3);
  • Step 3 the compound of formula (II-3) is coupled by Suzuki, in the presence of a coupling agent such as Pd(dtbpf)Cl 2 /H 3 PO 4 , and heated in a solvent such as dioxane/water to obtain formula (II- 4) compound;
  • a coupling agent such as Pd(dtbpf)Cl 2 /H 3 PO 4
  • a solvent such as dioxane/water
  • Step 4 reacting the compound of formula (II-4) with amine under the action of a catalyst such as RuPhos-G2, in the presence of a base such as cesium carbonate, and heating in a solvent such as toluene to obtain a compound of formula (II-4);
  • a catalyst such as RuPhos-G2
  • a base such as cesium carbonate
  • Step 5 the compound of formula (II-5) is deprotected under the action of acid such as HCl to obtain the compound of formula (II);
  • R 1 , R 2 , and X are as defined above for general formula (I):
  • Step 1 the compound of formula (III-1) reacts with a chlorination reagent such as POCl3 by heating to obtain the compound of formula (III-2);
  • Step 2 reacting the compound of formula (III-2) with amine in the presence of a base such as K 2 CO 3 in a solvent such as DMF at about room temperature to obtain a compound of formula (III-3);
  • Step 3 reacting the compound of formula (III-3) with amine in the presence of a base such as DIEA and heating in a solvent such as DMF to obtain a compound of formula (III-4);
  • Step 4 The compound of formula (III-4) reacts with a cyanating agent such as Zn(CN) 2 , in the presence of a catalyst such as Pd 2 (dba) 3 /DPPF, and in the presence of a solvent such as DMF, to obtain formula (III-5 ) compounds;
  • a cyanating agent such as Zn(CN) 2
  • a catalyst such as Pd 2 (dba) 3 /DPPF
  • a solvent such as DMF
  • Step 5 the compound of formula (III-5) is reacted in a solvent such as MeOH/THF in the presence of a catalyst such as Raney nickel/ammonia water to obtain a compound of formula (III-6) through reduction reaction;
  • Step 6 the compound of formula (III-6) is reacted in a solvent such as DME in the presence of a condensing agent such as HATU/DIEA to obtain a compound of formula (III-7) through condensation reaction;
  • Step 7 The compound of formula (III-7) is ring-closed by heating eg at 100-150° C. in the presence of POCl 3 to obtain the compound of formula (III).
  • Step 1 the compound of formula (IV-1) reacts with a formate such as ethyl formate in a solvent such as THF under the action of a base such as LDA at low temperature to obtain a compound of formula (IV-2);
  • Step 2 reacting the compound of formula (IV-2) with 3-hydrazine-1H-pyrazole in a solvent such as ethanol at room temperature to obtain the compound of formula (IV-3);
  • Step 3 ring-closing reaction of the compound of formula (IV-3) in a solvent such as NMP at elevated temperature such as reflux to obtain the compound of formula (IV-4);
  • Step 4 reacting the compound of formula (IV-4) with amine in a solvent such as DMSO by heating to obtain the compound of formula (IV-5);
  • Step 5 Add a protecting group to the compound of formula (IV-5) with a protecting reagent such as DHP/TsOH in a solvent such as DCM at room temperature to obtain a compound of formula (IV-6);
  • a protecting reagent such as DHP/TsOH in a solvent such as DCM
  • Step 6 the compound of formula (IV-6) is heated in a solvent such as NMP in the presence of a coupling agent such as Pd(dtbpf)Cl 2 /CsCO 3 , and coupled with an amine to obtain a compound of formula (IV-7);
  • a solvent such as NMP
  • a coupling agent such as Pd(dtbpf)Cl 2 /CsCO 3
  • Step 7 The compound of formula (IV-7) is deprotected to obtain the compound of formula (IV).
  • the experimental materials and reagents used in the following examples can be obtained from commercial sources, prepared according to methods in the prior art or prepared according to methods similar to those disclosed in the present application unless otherwise specified.
  • the raw materials used in the present invention are all commercially available raw materials, which can be used directly without further purification, wherein the 5,7-dichloropyrazolo[1,5-A]pyrimidine used in the following examples was purchased from Shanghai Haohong Biomedical Technology Co., Ltd. (Leyan, CAS: 57489-77-7, batch number: Ld102321002), 8-bromo-6-chloroimidazo[1,2-B]pyridazine was purchased from Shaoyuan Technology ( Shanghai) Co., Ltd.
  • column chromatography adopts silica gel (300-400 mesh) produced by Rushan Sun Desiccant Co., Ltd.; thin-layer chromatography adopts GF254 (0.25 mm); nuclear magnetic resonance chromatography (NMR) uses Varian- 400 nuclear magnetic resonance instrument for determination; liquid mass spectrometry (LC/MS) uses Agilent TechnologiESI 6120 liquid mass spectrometry instrument.
  • Step 4 3-(7-((R)-3-Methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) Synthesis of pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 5 3-(7-((R)-3-Methylmorpholino)-3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl) Synthesis of -8-oxa-3-azabicyclo[3.2.1]octane
  • Step 4 3-(8-((R)-3-Methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) Synthesis of imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 5 3-(8-((R)-3-methylmorpholino)-3-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl) Synthesis of -8-oxa-3-azabicyclo[3.2.1]octane
  • Step 4 6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-3-methylmorpholino)pyridazine-3-carba Nitrile synthesis
  • Step 5 (6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-3-methylmorpholino)pyridazine-3- base) synthesis of methylamine
  • Step 6 N-((6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-((R)-3-methylmorpholino)pyridazine- Synthesis of 3-yl)methyl)-1H-pyrazole 5-carboxamide
  • Step 7 3-(4-((R)-3-Methylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl) Synthesis of -8-oxa-3-azabicyclo[3.2.1]octane
  • the reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution at 0°C, and then adjusted to pH 9 with a saturated sodium bicarbonate solution at 0°C, then washed with EA (200mL ⁇ 3 ) extraction, the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was reversed-phase preparative chromatography twice (acetonitrile/water contained 0.05% ammonia) and (acetonitrile/water contained 0.05% formic acid) Separation and purification gave the target compound (1.50g, yield 22.2%, green solid).
  • 3-aminopyrazole (1.00g, 12.0mmol) was added to 6mol/L hydrochloric acid aqueous solution (7mL), the mixture was cooled to -5°C, and 1mol/L sodium nitrite aqueous solution (12mL, 12.0 mmol), the reaction solution was stirred and reacted at room temperature for 2 hours.
  • a concentrated hydrochloric acid solution 24mL of stannous chloride dihydrate (5.43g, 24.1mmol) was added to the reaction mixture, and the reaction solution was stirred at room temperature for 1 hour, then concentrated under reduced pressure to obtain the crude product of the target compound (9.00g, Crude product, bright yellow solid).
  • Step 2 Synthesis of 3-((2-(1H-pyrazolyl-3-yl)hydrazino)methyl)-2,6-difluoro-4-iodopyridine
  • Step 5 3-(4-Iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b] Synthesis of pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 6 3-(4-((R)-3-Methylmorpholino)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl) Synthesis of -1H-pyrazol[3,4-b]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 7 3-(4-((R)-3-Methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridine-6- Synthesis of -8-oxa-3-azabicyclo[3.2.1]octane
  • Step 3 4-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octane- Synthesis of 3-yl)pyridazine-3-carbonitrile
  • Step 4 (4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octane Synthesis of -3-yl)pyridazin-3-yl)methanamine
  • Step 5 N-((4-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-6-(8-oxa-3-azabicyclo[3.2.1 Synthesis of ]octane-3-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide
  • Step 6 3-(4-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-7-(1H-pyrazol-3-yl)imidazol[1,5- b] Synthesis of pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 4 Synthesis of (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-morpholinopyridazin-3-yl)methanamine
  • Step 5 N-((6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-morpholinopyridazin-3-yl)methyl)-1H -Synthesis of pyrazole-5-carboxamide
  • Step 7 3-(4-Morpholino-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-aza Synthesis of Bicyclo[3.2.1]octane
  • Example 8 8-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-7-(1H-pyrazol-3-yl)imidazol[1,5 -b]pyridazin-4-yl)-3- Oxa-8-azabicyclo[3.2.1]octane
  • LC-MS (ESI) m/z 259.9 [M+H] + , 261.9 [M+2+H] + .
  • Step 2 8-(6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropyrazin-4-yl)-3-oxa-8- Synthesis of azabicyclo[3.2.1]octane
  • LC-MS (ESI) m/z 337.0 [M+H] + .
  • LC-MS (ESI) m/z 328.0 [M+H] + .
  • Step 4 (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3-oxa-8-azabicyclo[3.2.1]octane Synthesis of -8-yl)pyridazin-3-yl)methanamine
  • Step 5 N-((6-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-4-(3-oxa-8-azabicyclo[3.2.1 Synthesis of ]octane-8-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide
  • Step 6 8-(2-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-7-(1H-pyrazol-3-yl)imidazol[1,5- b] Synthesis of pyridazin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane
  • LC-MS (ESI) m/z 346.9 [M+H] + .
  • LC-MS (ESI) m/z 424.2 [M+H] + .
  • LC-MS (ESI) m/z 415.0 [M+H] + .
  • Step 4 (3R)-4-(3-(Aminomethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)pyridazin-4-yl) Synthesis of tert-butyl 3-methylpiperazine-1-carboxylate
  • Step 6 3-(4-((R)-2-Methylpiperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazine-2 Synthesis of -yl)-8-oxa-3-azabicyclo[3.2.1]octane formate
  • Step 1 Synthesis of tert-butyl 4-(3,6-dichloropyridazin-4-yl)piperazine-1-carboxylate
  • Step 2 4-(6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropyridazin-4-yl)piperazine-1-carboxylic acid Synthesis of tert-butyl ester
  • Step 3 4-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-cyanopyridazin-4-yl)piperazine-1-carboxy Synthesis of tert-butyl ester
  • LC-MS (ESI) m/z 401.1 [M+H] + .
  • Step 4 4-(3-(Aminomethyl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyridazin-4-yl)piperazine-1- Synthesis of tert-Butyl Carboxylate
  • Step 5 4-(3-((1H-pyrazole-5-carboxamide)methyl)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyridazine Synthesis of -4-yl)piperazine-1-carboxylate tert-butyl ester
  • Step 6 3-(4-(Piperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa Synthesis of -3-azabicyclo[3.2.1]octane formate
  • Step 2 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-2,4-dimethylpiperazin-1-yl) Synthesis of pyridazine-3-carbonitrile
  • Step 3 (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-2,4-dimethylpiperazin-1-yl ) Synthesis of pyridazin-3-yl)methylamine
  • Step 4 N-((6-(8-Oxy-3-azabicyclo[3.2.1]octan-3-yl)-4-((R)-2,4-Dimethylpiperazine- Synthesis of 1-yl)pyrazin-3-yl)methyl)-1H-pyrazole-5-carboxamide
  • Step 5 3-(3-Chloro-4-((R)-2,4-dimethylpiperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5 -b] Synthesis of pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 6 3-(4-((R)-2,4-Dimethylpiperazin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridine Synthesis of oxazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane carboxylate
  • Step 2 3-(4-iodo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b Synthesis of ]pyridin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 3 3-(6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(tetrahydro-2H-pyran-2-yl) Synthesis of -1H-pyrazol-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 4 3-(6-(8-Oxa-3-azabicyclo[3.2.1]octane-3-yl)-1-(1H-pyrazol-3-yl)-1H-pyrazol[ Synthesis of 3,4-b]pyridin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 1 Synthesis of methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate
  • Step 2 4-((1-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)ethylidene)amino)-1-methyl-1H-pyrazole-5 -Synthesis of methyl formate
  • Step 3 5-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridine-7- Alcohol synthesis
  • Step 4 3-(7-Chloro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane Alkane
  • Step 5 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[4,3-b]pyridine Synthesis of -5-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 6 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-bromo-1-methyl-1H-pyrazolo[4,3 -b] Synthesis of pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 7 3-(7-(8-oxa-3-azabicyclo[3.2.1]octyl)-1-methyl-3-(1-(tetrahydro-2H-pyran-2-yl Synthesis of )-1H-pyrazol-3-yl)-1H-pyrazolyl[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 8 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-3-(1H-pyrazol-3-yl)- Synthesis of 1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 3 6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(4,4-difluoropiperidin-1-yl)pyridazine-3-carba Nitrile synthesis
  • Step 4 (6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(4,4-difluoropiperidin-1-yl)pyridazine-3- base) synthesis of methylamine
  • Step 5 N-((6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(4,4-difluoropiperidin-1-yl)pyridazine Synthesis of -3-yl)methyl)-1H-pyrazole-5-carboxamide
  • Step 6 3-(4-(4,4-Difluoropiperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl Synthesis of )-8-oxa-3-azabicyclo[3.2.1]octane
  • reaction solution was slowly added dropwise to a saturated sodium bicarbonate solution at 0°C, and then the pH was adjusted to 9 with a saturated sodium bicarbonate solution at 0°C, and then washed with EA (40.0 mL ⁇ 3) extraction, the combined organic layer was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by reverse-phase preparative chromatography (acetonitrile/water containing 0.05% formic acid) to obtain the target compound (127.46 mg, recovered rate 40.3%, gray solid).
  • LC-MS (ESI) m/z 416.1 [M+H] + .
  • Step 4 (6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-((S)-3-methylmorpholino)pyridazin-3-yl ) Synthesis of methylamine
  • Step 6 3-(4-((S)-3-methylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl) Synthesis of -8-oxa-3-azabicyclo[3.2.1]octane
  • Step 3 6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(cis-2,6-dimethylmorpholino)pyridazine-3-carba Nitrile synthesis
  • Step 4 (6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(cis-2,6-dimethylmorpholino)pyridazine-3- base) synthesis of methylamine
  • Step 5 N-((6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-4-(cis-2,6-dimethylmorpholino)pyridazine Synthesis of -3-yl)methyl)-1H-pyrazole-5-carboxamide
  • Step 6 3-(4-(cis-2,6-dimethylmorpholino)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl Synthesis of )-8-oxa-3-azabicyclo[3.2.1]octane
  • LC-MS (ESI) m/z 232.1 [M+H] + .
  • Step 2 Synthesis of 3-(6-chloro-5-(piperidin-1-yl)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 3 Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(piperidin-1-yl)pyridazine-3-carbonitrile
  • LC-MS (ESI) m/z 300.2 [M+H] + .
  • Step 4 (6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(piperidin-1-yl)pyridazin-3-yl)methanamine synthesis
  • Step 6 3-(4-(Piperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa Synthesis of -3-azabicyclo[3.2.1]octane
  • LC-MS (ESI) m/z 380.1 [M+H] + .
  • LC-MS (ESI) m/z 248.1 [M+H] + .
  • LC-MS (ESI) m/z 225.1 [M+H] + .
  • Step 3 Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(2-methylmorpholino)pyridazine-3-carbonitrile
  • LC-MS (ESI) m/z 316.0 [M+H] + .
  • LC-MS (ESI) m/z 396.1 [M+H] + .
  • Step 3 3-(1-Methyl-7-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole Synthesis of -3-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 4 3-(1-Methyl-7-((R)-3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3- b] Synthesis of pyridin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 2 3-(6-Chloro-5-(3,3-dimethylmorpholino)pyridazin-3-yl)-8-oxa-3-azabicyclo[3.2.1]octane synthesis
  • LC-MS (ESI) m/z 330.2 [M+H] + .
  • Step 4 (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(3,3-dimethylmorpholino)pyridazin-3-yl ) Synthesis of methylamine
  • Example 23 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-3-(1H-pyrazol-5-yl )pyrazolo[1,5-a]pyrimidine -7-yl)tetrahydro-2H-pyran-4-ol
  • LC-MS (ESI) m/z 231.1 [M+H] + .
  • Step 2 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazol[1,5-a]pyrimidine-7- base) synthesis of tetrahydro-2H-pyran-4-ol
  • Step 3 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-iodopyrazol[1,5-a] Synthesis of pyrimidin-7-yl)tetrahydro-2H-pyran-4-ol
  • Step 4 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-3-(1-(tetrahydro-2H-pyridine Synthesis of pyran-2-yl)-1H-pyrazol-5-yl)pyrazol[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ol
  • Step 5 4-(5-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-3-(1H-pyrazol-5-yl) Synthesis of pyrazol[1,5-a]pyrimidin-7-yl)tetrahydro-2H-pyran-4-ol
  • LC-MS (ESI) m/z 311.2 [M+H] + .
  • Step 3 3-(3-iodo-7-(1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3 -Synthesis of azabicyclo[3.2.1]octane
  • Step 4 3-(7-(1-Methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3- Synthesis of yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 5 3-(7-(1-Methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-5- Synthesis of -8-oxa-3-azabicyclo[3.2.1]octane
  • Step 3 6-Chloro-8-(1-methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3 -Synthesis of imidazo[1,2-b]pyridazine
  • Step 4 3-(8-(1-Methyl-1H-pyrazol-5-yl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3- Synthesis of imidazo[1,2-b]pyridazin-6-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 5 3-(8-(1-Methyl-1H-pyrazol-5-yl)-3-(1H-pyrazol-3-yl)imidazo[1,2-b]pyridazine-6- Synthesis of -8-oxa-3-azabicyclo[3.2.1]octane
  • Step 1 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8- Synthesis of Oxa-3-azabicyclo[3.2.1]octane
  • Step 2 3-(7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-iodopyrazol[1,5-a]pyrimidin-5-yl) Synthesis of -8-oxa-3-azabicyclo[3.2.1]octane
  • Step 3 3-(7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(1-(tetrahydro-2H-pyran-2-yl) Synthesis of -1H-pyrazol-5-yl)pyrazol[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 4 3-(7-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-3-(1H-pyrazol-5-yl)pyrazol[1,5 Synthesis of -a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Example 29 1-((R)-4-(2-((1R,S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-7-(1H -pyrazol-3-yl)imidazol[1,5- b] pyridazin-4-yl)-3-methylpiperazin-1-yl)ethane-1-one
  • Step 3 Synthesis of (R)-1-(4-(3,6-dichloropyridazin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one
  • Step 4 1-((3R)-4-(6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-chloropyridazin-4-yl)- Synthesis of 3-methylpiperazin-1-yl)ethan-1-one
  • Step 5 4-((R)-4-Acetyl-2-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl ) Synthesis of pyridazine-3-carbonitrile
  • LC-MS (ESI) m/z 357.0 [M+H] + .
  • Step 6 1-((3R)-4-(3-(Aminomethyl)-6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridazine-4 Synthesis of -yl)-3-methylpiperazin-1-yl)ethan-1-one
  • Step 7 N-((4-((R)-4-acetyl-2-methylpiperazin-1-yl)-6-(8-oxa-3-azabicyclo[3.2.1]octane Synthesis of alk-3-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide
  • Step 8 1-((R)-4-(2-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-7-(1H- Synthesis of pyrazol-3-yl)imidazol[1,5-b]pyridazin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one
  • LC-MS (ESI) m/z 359.0 [M+H] + .
  • Step 4 6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(4,4-difluoro-2-methylpiperidin-1-yl) Synthesis of pyridazine-3-carbonitrile
  • LC-MS (ESI) m/z 350.1 [M+H] + .
  • Step 5 (6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(4,4-difluoro-2-methylpiperidin-1-yl ) Synthesis of pyridazin-3-yl)methylamine
  • Step 6 N-((6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-(4,4-difluoro-2-methylpiperidine- Synthesis of 1-yl)pyridazin-3-yl)methyl)-1H-pyrazole-5-carboxamide
  • Step 7 3-(4-(-4,4-Difluoro-2-methylpiperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b] Synthesis of pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Examples 31 and 32 3-(4-((R)-4,4-difluoro-2-methylpiperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[ 1,5-b]pyridazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane, and 3-(4-((S)-4,4-difluoro- 2-Methylpiperidin-1-yl)-7-(1H-pyrazol-3-yl)imidazo[1,5-b]pyridazin-2-yl)-8-oxa-3-aza Bicyclo[3.2.1]octane
  • Example 34 1-((R)-4-(6-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-1-(1H -pyrazol-3-yl)-1H- Pyrazol[3,4-b]pyridin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one
  • Step 1 1-((R)-4-(6-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-1-(1- (Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolyl[3,4-b]pyridin-4-yl)-3-methylpiperazine- Synthesis of 1-yl)ethan-1-one
  • Step 2 1-((R)-4-(6-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-1-(1H- Synthesis of pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one
  • Step 1 (4-(6-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-1-(1-(tetrahydro-2H- Synthesis of pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazol[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol
  • Step 2 (4-(6-((1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-1-(1H-pyrazol-3-yl Synthesis of )-1H-pyrazol[3,4-b]pyridin-4-yl)morpholin-3-yl)methanol
  • Step 4 3-(7-(3,3-Dimethylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridine Synthesis of Azol[1,5-a]pyrimidin-5-yl)-8-oxa-3-azabicyclo[3.2.1]octane
  • Step 5 3-(7-(3,3-Dimethylmorpholino)-3-(1H-pyrazol-5-yl)pyrazol[1,5-a]pyrimidin-5-yl)-8 -Synthesis of oxa-3-azabicyclo[3.2.1]octane
  • the homogeneous time-resolved fluorescence technique from Cisbio was used in this experiment to test.
  • test compound solutions Prepare the solutions of the compounds of the examples shown in the table below using DMSO as a solvent, and the stock solution is usually 10 mM.
  • the maximum initial concentration was 3 ⁇ M
  • DMSO was serially diluted 3 times
  • a total of 10 concentrations were added to the corresponding wells of a 384-well plate (geriner bio-one, Cat#784075)
  • the final concentrations were 3000, 1000, 333, 111, 37, 12.3, 4.12, 1.37, 0.457, 0.152nM, add the corresponding amount of DMSO to other wells to be used as negative control wells or positive control wells respectively.
  • anti-phospho-p53-Eu acts as an energy donor to specifically bind to the phosphorylation site on p53
  • anti-GST-d2 acts as an energy
  • the receptor can specifically bind to the GST tag carried on p53. If excited by a laser with a certain wavelength (the wavelength of the excitation light in this experiment is 340nm), the energy donor can emit light with a wavelength of 615nm. Linked to p53), energy transfer can occur between the energy donor and the energy acceptor, so that the energy acceptor emits emission light with a wavelength of 665nm. Use a plate reader to detect the two emitted lights and calculate the ratio of the two signals at 665nm and 615nm, and calculate the IC 50 of the sample to be tested by drawing and calculating.
  • HTRF detection buffer (Cisbio, Cat#62SDBRDF, Lot#17A), as shown in the following table:
  • Detection Reagent source Dilution factor Mother liquor concentration anti-phospho-p53-Eu Cisbio,Cat#61P08KAZ 400 400 units anti-GST-d2 Cisbio, Cat#61GSTDLB 200 200 units
  • Inhibition rate of single well 1-(signal value of single well-average signal value of positive control)/(average signal value of negative control-average signal value of positive control)
  • the inhibition rate of compound pores can be calculated.
  • Inhibition rate minimum response+(compound concentration ⁇ curve slope)*(highest response-minimum response)/(compound concentration ⁇ curve slope+half inhibitory concentration ⁇ curve slope)
  • ATR IC50 (nM) compound number ATR IC50 (nM) compound number.
  • ATR IC50 (nM) 1 17.4 16 21.9 2 40.3 17 32.0 3 5.9 18 50.8 4 20.3 26 57.7 5 8.2 27 149.0 6 13.2 20 1.4 7 21.4 twenty three 85.5

Abstract

L'invention concerne un groupe de composés de 8-oxa-3-azabicyclo[3.2.1]octane de formule (I) utilisés en tant qu'inhibiteurs d'ATR, et leur procédé de préparation, une composition pharmaceutique les contenant, et leur utilisation dans le traitement ou la prévention de maladies associées à l'ATR.
PCT/CN2022/107932 2021-07-27 2022-07-26 Composé de 8-oxo-3-azabicyclo[3.2.1]octane ou sel de celui-ci, procédé pour le préparer et son utilisation WO2023005928A1 (fr)

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IL310412A IL310412A (en) 2021-07-27 2022-07-26 8-oxa-3-aza-dicyclo[3.2.1]octane compounds or their salt, method of preparation, and their use
CA3227713A CA3227713A1 (fr) 2021-07-27 2022-07-26 Compose de 8-oxa-3-azabicyclo[3.2.1]octane ou sel de celui-ci, procede pour le preparer et son utilisation
AU2022316931A AU2022316931A1 (en) 2021-07-27 2022-07-26 8-oxo-3-azabicyclo[3.2.1]octane compound or salt thereof, and preparation method therefor and use thereof

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016020320A1 (fr) 2014-08-04 2016-02-11 Bayer Pharma Aktiengesellschaft 2- (morpholin -4-yl)-l,7-naphtyridines
WO2017202748A1 (fr) 2016-05-24 2017-11-30 Merck Patent Gmbh Dérivés hétérocycliques tricycliques
WO2020049017A1 (fr) 2018-09-07 2020-03-12 Merck Patent Gmbh Dérivés de 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine
WO2020087170A1 (fr) 2018-10-30 2020-05-07 Repare Therapeutics Inc. Composés, compositions pharmaceutiques, procédés de préparation de composés et leur utilisation en tant qu'inhibiteurs de kinase atr
CN111848605A (zh) 2019-04-30 2020-10-30 四川科伦博泰生物医药股份有限公司 一种取代吡啶并[3,4-b]吡嗪-2(1H)-酮化合物、其制备方法和用途
CN112142744A (zh) * 2019-06-28 2020-12-29 上海瑛派药业有限公司 取代的稠合杂芳双环化合物作为激酶抑制剂及其应用
WO2021012049A1 (fr) * 2019-07-22 2021-01-28 Repare Therapeutics Inc. Dérivés 2-morpholinopyridine substitués utilisés en tant qu'inhibiteurs de kinases atr
WO2022028598A1 (fr) * 2020-08-07 2022-02-10 Shanghai Antengene Corporation Limited Inhibiteurs d'atr et leurs utilisations

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016020320A1 (fr) 2014-08-04 2016-02-11 Bayer Pharma Aktiengesellschaft 2- (morpholin -4-yl)-l,7-naphtyridines
WO2017202748A1 (fr) 2016-05-24 2017-11-30 Merck Patent Gmbh Dérivés hétérocycliques tricycliques
WO2020049017A1 (fr) 2018-09-07 2020-03-12 Merck Patent Gmbh Dérivés de 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine
WO2020087170A1 (fr) 2018-10-30 2020-05-07 Repare Therapeutics Inc. Composés, compositions pharmaceutiques, procédés de préparation de composés et leur utilisation en tant qu'inhibiteurs de kinase atr
CN111848605A (zh) 2019-04-30 2020-10-30 四川科伦博泰生物医药股份有限公司 一种取代吡啶并[3,4-b]吡嗪-2(1H)-酮化合物、其制备方法和用途
CN112142744A (zh) * 2019-06-28 2020-12-29 上海瑛派药业有限公司 取代的稠合杂芳双环化合物作为激酶抑制剂及其应用
WO2021012049A1 (fr) * 2019-07-22 2021-01-28 Repare Therapeutics Inc. Dérivés 2-morpholinopyridine substitués utilisés en tant qu'inhibiteurs de kinases atr
WO2022028598A1 (fr) * 2020-08-07 2022-02-10 Shanghai Antengene Corporation Limited Inhibiteurs d'atr et leurs utilisations

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ANSEL, HOWARD C ET AL.: "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems", 2004, LIPPINCOTT, WILLIAMS & WILKINS
BERGE ET AL., PHARM SCL, vol. 66, 1977, pages 1 - 19
DI, LI ET AL.: "Optimization of a Higher Throughput Microsomal Stability Screening Assay for Profiling Drug Discovery Candidates", J. BIOMOL. SCREEN, vol. 8, no. 4, 2003, pages 453, XP002670661, DOI: 10.1177/1087057103255988
KERNS, EDWARD HDI LI: "Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization", 2008, ACADEMIC PRESS
no. 1876467-74-1

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